Stroke is the leading cause of adult disability and the third cause of death worldwide. In the United States alone, a person has a stroke every 45 seconds, which accounts for approximately 700,000 people per year. Stroke is the third leading cause of death in the U.S., and it can lead to severe, long-term disability. In fact, more than two-thirds of stroke survivors are left with significant sensorimotor impairment. Stroke is a type of cardiovascular disease, which affects the arteries leading to and within the brain. When a stroke occurs, part of the brain starts to die from lack of blood flow and the part of the body it controls is affected. Damage to the brain can cause loss of speech, vision, or movement in an arm or a leg, depending on the part of the brain that is affected. Treatments are available to minimize the potentially devastating effects of stroke, but to receive them one must recognize the warning signs and act quickly.
A stroke occurs when a blood vessel that carries oxygen and nutrients to the brain is either blocked by a clot or bursts. Clots that block an artery cause ischemic strokes, which account for about 70-80 percent of all strokes. Cerebral ischemia induced by stroke leads to rapid death of neurons and vascular structures in the supplied region of the brain. The loss of neurons, arterioles, and capillaries in the infarcted zone is irreversible and results in the formation of scar tissue over time. For this reason, most experimental and clinical therapies have mainly focused on limiting infarct size. Attempts to replace the necrotic zone of the brain by transplanting fetal brain cells and other stems cells have been done, and although these attempts have been successful in the survival of many of the grafted cells, they have invariably failed to reconstitute healthy neurons and cerebral vessels integrated structurally and functionally with the spared cerebral tissue.
Recently, bone marrow stem cells (BMSC) have been shown to have the capacity to colonize various tissues, proliferate, and differentiate into cell lineages of the host organ. BMSC have also been shown to be able to differentiate into neuronal cells (Mezey et al., Science 290:1779-1782, 2000). Moreover, brain injury has been shown to be sensed by distant stem cells with BMSC migration to the injured area of the brain and subsequent differentiation (Brazelton et al., Science 290:1775, 2000). Brazelton et al. (supra) showed the generation of neuronal phenotypes in the adult brain of mice after an adult bone marrow transplant; hundreds of marrow-derived cells in brain sections expressed gene products typical of neurons. Weimann et al. (Proc. Natl. Acad. Sci. USA 100:2088-2093, 2003) confirmed that BMSC could cross the blood-brain barrier and contribute to the neurons in the brain by their study of male sex chromosomes in Purkinje neurons in the brain of female patients at autopsy who had received bone marrow transplants from male donors. Hess et al. (Stroke 33:1362-1368, 2002) also showed that BMSC incorporated into the vasculature in the ischemic zone after middle cerebral artery occlusion (MCAO) and expressed an endothelial cell and neuronal cell markers. Adult whole bone marrow, prelabeled with bromodeoxyuridine (BrdU), was transplanted into the ischemic boundary zone of the adult rat brain after MCAO and later expressed neuronal and astrocytic proteins, suggesting that intracerebral transplantation of bone marrow could potentially be used to induce plasticity in the ischemic brain (Li et al., Cell Transplant 10:31-40, 2001).
BMSC are known to be stimulated by various cytokines. Granulocyte colony stimulating factor (G-CSF) has been found to be useful, alone or in combination with stem cell factor (SCF), in the mobilization of BMSC. G-CSF and SCF have recently been used to increase the mobilization of BMSC into organs for tissue repair (Orlic et al., Proc. Natl. Acad. Sci. USA 98:10344-10349, 2001). The findings by Orlic et al. (supra) in a mouse model of acute myocardial infarction, induced by coronary artery ligation, suggested that the mobilization of primitive BMSC by these cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of acute myocardial infarction or other pathology. Other researchers have used G-CSF treatment after MCAO and demonstrated that this cytokine increases short-term survival and decreases infarct volume in mice four days after the ischemic event (Six et al., Eur. J. Pharmacol. 458:327-328, 2003). In another short-term study using the in vivo administration of G-CSF at the time of MCAO in rats, short-term survival rate increased and infarct volume decreased (Schabitz et al., Stroke 34:745-751, 2003). Schabitz et al. (supra) also showed that G-CSF had a neuroprotective effect on mouse cerebellar granule cells in culture. These studies suggest that G-CSF provides a protective effect to the brain after cerebral ischemia.
G-CSF causes an increase in the release of hematopoietic stem cells into the blood, and plays a role in the proliferation, differentiation, and survival of myeloid progenitor cells (Takano et al., Curr. Pharm. Des. 9:1121-1127, 2003). G-CSF is also useful, alone or in combination with other compounds, such as other cytokines, for growth or expansion of cells in culture (for example, for bone marrow transplants or ex vivo expansion).
It is evident that treatment with G-CSF shows promise in inducing BMSC to travel to the injured brain to minimize the potentially devastating effects of stroke. However, for this treatment to be effective, one must recognize the warning signs and act quickly. Thus, there is a need in the art to develop quick, easy, and effective treatments for cerebral ischemia. Accordingly, an object of the present invention is to provide such methods for the treatment of cerebral ischemia and other neurological disorders, which are discussed in further detail herein. The present invention provides the first functional studies demonstrating that treatment with SCF, alone and in combination with G-CSF, provides a regenerative, as well as protective, effect on neurological function after cerebral ischemia. The present invention also provides the first demonstration that this cytokine treatment actually improves neurological function after an ischemic event. Additionally, the present invention provides evidence that this cytokine treatment could restore impaired brain function even when administered during the chronic stage of stroke.